1. THALASSEMIAS Alpha or beta chains deficient synthesis involved
A WIDE VARIETY of diseases involving GLOBIN synthesis, COMPLEX genetics
Alpha or beta chains deficient synthesis involved
Often termed MAJOR or MINOR, depending on severity, silent carriers and “traits” are seen
HEMOLYSIS is uniformly a feature, and microcytic anemia, i.e, LOW MCV (just like iron deficiency anemia has a low MCV)
A “crew cut” skull x-ray appearance may be seen in severe erythroid hyperplasia.

2. Note the “spiculated” or “spiked” appearance of the outer table of the skull due to extreme erythroid hyperplasia! How is this different from a myeloma skull?

3. Hemoglobin H Disease Deletion of THREE alpha chain genes
HGB-H is primarilly Asian
HGB-H has a HIGH affinity for oxygen
HGB-H is unstable and therefore has classical hemolytic behavior
H= High affinity
Why is HIGH AFFINITY bad? Sucks in the O2 very readily, but won’t give it up to the tissues!

4. HYDROPS FETALIS
FOUR alpha chain genes are deleted, so this is the MOST SEVERE form of thalassemia
Many/most never make it to term
Children born will have a SEVERE hemolytic anemia as in the erythroblastosis fetalis of Rh disease:
Pallor (as in all anemias), jaundice, kernicterus
Edema (hence the name “hydrops”)
Massive hepatosplenomegaly (hemolysis)
NOT all hydrops fetalis is RH antigen related, is it?

5. Paroxysmal Nocturnal Hemoglobinuria (PNH)
GlycosylphosPhatidylInositol (lipid rafts)
ACQUIRED, NOT INHERITED like all the previous hemolytic anemias were
ACQUIRED mutations in phosphatidylinositol glycan A (PIGA)
Note: It is “P” and “N” only 25% of the time!
Phosphatidylinositol N-acetylglucosaminyltransferase subunit A is an enzyme that in humans is encoded by the PIGA gene.
PIGA makes GPI, defective PIGA makes defective or inadequate GPI. Why does the term hemoglobinuria imply hemolysis? What does “paroxysmal” mean” Ans: Sudden, UN-controllable, like a seizure
----- Meeting Notes (7‏/4‏/16 00:58) -----

6. Immunohemolytic Anemia
All of these have the presence of antibodies and/or compliment present on RBC surfaces
NOT all are AUTOimmune, some are caused by drugs
Antibodies can be
WARM (IgG)
COLD AGGLUTININ (IgM)
COLD HEMOLYSIN (paroxysmal) (IgG)
AHA is a bad term because not all are autoimmune, but caused by drugs.

7. IMMUNOHEMOLYTIC ANEMIAS
WARM AGGLUTININS (IgG), will NOT agglutinate at room temp
Primary Idiopathic (most common)
Secondary (Tumors, especially leuk/lymph, drugs)
COLD AGGLUTININS: (IgM), WILL agglutinate at room temp
Mycoplasma pneumoniae, HIV, mononucleosis
COLD HEMOLYSINS: (IgG) Cold Paroxysmal Hemoglobinuria, hemo-LYSIS in body, ALSO often follows mycoplasma pneumoniae
What is the difference between an “agglutinin” and a “hemolysin”? Ans: “-lysis” implies complement fixation.
The most common drugs to cause warm agglutinins are anti-microbials (e.g., cefotetan, ceftriaxone and piperacillin).

8. COOMBS TEST DIRECT: Patient’s CELLS are tested for surface Ab’s
INDIRECT: Patient’s SERUM is tested for Ab’s.
The Coombs is a routine test used in the workup of just about ALL kinds of hemolytic anemias

9. HEMOLYSIS/HEMOLYTIC ANEMIAS DUE TO RBC TRAUMA
Mechanical heart valves breaking RBC’s
MICROANGIOPATHIES:
TTP
Hemolytic Uremic Syndrome
HUS often follows an E. Coli enteric infection in kids, and is a associated with a wide variety of disorders in adults, most closely linked to TTP.

10. NON-Hemolytic Anemias: i.e., DE-creased Production
“Megaloblastic” Anemias
B12 Deficiency (Pernicious Anemia)
Folate Deficiency
Iron Deficiency
Anemia of Chronic Disease
Aplastic Anemia
“Pure” Red Cell Aplasia
OTHER forms of Marrow Failure
Anemias of diminished erythropoesis. Doesn’t this just really boil down to three items?

11. MEGALOBLASTIC ANEMIAS
Differentiating megaloblasts (marrow) from macrocytes (peripheral smear, MCV>94)
Impaired DNA synthesis
For all practical purposes, also called the anemias of B12 and FOLATE deficiency
Often VERY hyperplastic/hypercellular marrow
Megaloblasts on top, macrocytes on bottom. What is the difference between a megaloblast and a macrocyte? What is the difference between a megaloblast and an erythroblast? Do the arrows point to macrocytes, i.e., RBCs with a high MCV. Why is it silly to say a single RBC has a high MCV?

12. Inadequate diet, vegetarianism Impaired absorption
Decreased intake
Inadequate diet, vegetarianism
Impaired absorption
Intrinsic factor deficiency  
Pernicious anemia    
Gastrectomy    
Malabsorption states  
Diffuse intestinal disease, e.g., lymphoma, systemic sclerosis
Ileal resection, ileitis  
Competitive parasitic uptake  
Fish tapeworm infestation    
Bacterial overgrowth in blind loops and diverticula of bowel
Increased requirement
Pregnancy, hyperthyroidism, disseminated cancer
This is the HARD way to remember megaloblastic anemias

13. Vit-B12 Physiology Oral ingestion
Combines with INTRINSIC FACTOR in the gastric mucosa
Absorbed in the terminal ileum
DEFECTS at ANY of these sites can produce a MEGALOBLASTIC anemia
This is the EASY way!
Now lets go back to the previous slide and it will all make sense!

14. ALL megaloblastic anemias are also MACROCYTIC (MCV>94 or MCV~100), and that not only are the RBC’s BIG and hyperplastic/hypercellular, but so are the neutrophils, and neutrophilic precursors in the bone marrow too, and even more so, HYPERSEGMENTED!!!
But are all macrocytic anemias megaloblastic? Hell NO!

15. PERNICIOUS ANEMIA MEGALOBLASTIC anemia LEUKOPENIA and HYPERSEGS
JAUNDICE
NEUROLOGIC posterolateral spinal tracts
ACHLORHYDRIA
Can’t absorb B12
LOW serum B12
Flunk Schilling test, i.e., can’t absorb B12, using a radioactive tracer
Why do neurologists carry tuning forks in their bags?
Why jaundice if PA is an anemia of impaired production rather than increased destruction? ANS: I don’t know!
Achlohydria: mean absence of hydrochric acid

16. FOLATE DEFICIENCY MEGALOBLASTIC AMEMIAS
Decreased Intake: diet, infancy
Impaired Absorption: intestinal disease
DRUGS: anticonvulsants, BCPs, CHEMO
Increased Loss: Hemodialysis
Increased Requirement: Pregnancy, infancy
Impaired Usage 

17. Fe Deficiency Anemia
Due to increased loss or decreased ingestion, almost always, nowadays, increased loss is the reason
Microcytic (low MCV), Hypochromic (low MCHC)
THE ONLY WAY WE CAN LOSE IRON IS BY LOSING BLOOD, because FE is recycled!
Is iron deficiency anemia the mother of all anemias? YES

18. Fe Transferrin Ferritin (GREAT test) Hemosiderin
A great diagram of the iron cycle. Know what heme, transferrin, ferritin, and hemosiderin are in the iron cycle.
Is serum FE a horrible test of iron deficiency anemia? YES
Is a serum FERRITIN a GREAT test for iron deficiency anemia? YES! Fe
Transferrin
Ferritin (GREAT test)
Hemosiderin

19. Clinical Fe-Defic-Anemia
Adult men: GI Blood Loss
PRE menopausal women: menorrhagia
POST menopausal women: GI Blood Loss

20. Relate hypochromia, microcytosis, anisocytosis to the Wintrobe indices: Ans: MCHC, MCV, RDW, respectively

21. 2 BEST lab tests: Serum Ferritin
Prussian blue hemosiderin stain of marrow (also called an “iron” stain)

22. Golden brown refractile pigment on H&E is HEMOSIDERIN when it stains BLUE by the Prussian Blue method!
Any marrow that has stuff staining with Prussian Blue, is NOT an iron deficiency!

23. Anemia of Chronic Disease*
CHRONIC INFECTIONS
CHRONIC IMMUNE DISORDERS
NEOPLASMS
LIVER, KIDNEY failure
Most are hypochromic (low MCHC), and microcytic (low MCV) like Fe deficiency anemias but have NORMAL iron stores (i.e., hemosiderin).
* Please remember these patients may very very much look like iron deficiency anemia, BUT, they have ABUNDANT STAINABLE HEMOSIDERIN in the marrow!

24. APLASTIC ANEMIAS
ALMOST ALWAYS involve platelet and WBC suppression as well
Some are idiopathic, but MOST are related to drugs, radiation
FANCONI’s ANEMIA is the only one that is inherited, and NOT acquired
Act at STEM CELL level, except for “pure” red cell aplasia
Fanconi syndrome and Fanconi anemia are two completely different disorders, but named after the same guy, even though the “syndrome was NOT described by him. Fanconi’s Anemia is characterized by short stature, skeletal anomalies, increased incidence of solid tumors and leukemias, bone marrow failure (aplastic anemia), and cellular sensitivity to DNA damaging agents such as mitomycin C.
If you understand the cell differentiation concept, why would an aplastic anemia be less likely to involve lymphocytes?

25. APLASTIC ANEMIAS
The NORMAL adult RED bone marrow in the axial skeleton should be about 50% cells and 50% fat. What is this?
Perhaps around 10:90?

26. APLASTIC ANEMIAS CHLORAMPHENICOL OTHER ANTIBIOTICS CHEMO INSECTICIDES
VIRUSES
EBV
HEPATITIS
Does this sound like the usual suspects again?
How about radiation? Sure, if enough axial skeleton is zapped!

27. MYELOPHTHISIC ANEMIAS
Are anemias caused by metastatic tumor cells replacing the bone marrow extensively

28. POLYCYTHEMIA Relative (e.g., hemoconcentration) Absolute
POLYCYTHEMIA VERA (Primary) (LOW EPO)
POLYCYTHEMIA (Secondary) (HIGH EPO)
HIGH ALTITUDE
EPO TUMORS
EPO “Doping”

29. P. VERA A “myeloproliferative” disease
ALL cell lines are increased, not just RBCs
What do you think the most serious consequence might be for a person with increased RBCs and platelets?

30. BLEEDING DISORDERS (aka, Hemorrhagic “DIATHESES”)
Blood vessel wall abnormalities √
Reduced platelets √
Decreased platelet function √
Abnormal clotting factors √
DIC (Disseminated INTRA-vascular Coagulation), also has ↓ plats.
Doesn’t this really boil down to TWO things? 1) Reduced platelet function/numbers, and, 2) everything else?

31. VESSEL WALL ABNORMALITIES (angiopathic thrombocytopenias) (NON-thrombotic cytopenic purpuras)
Infections, especially, meningococcemia, and rickettsia
Drug reactions causing a leukocytoclastic vasculitis
Scurvy, Ehlers-Danlos, Cushing syndrome
Henoch-Schönlein purpura (mesangial IgA deposits too)
Hereditary hemorrhagic telangiectasia (Osler–Weber–Rendu syndrome, Autosomal Dominant)
Amyloid
Normal platelets, but DAMAGED vessel walls, the so-called “angiopathic” thrombocytopenias.

32. THROMBOCYTOPENIAS Like RBCs: Normal value 150K-300K
DE-creased production
IN-creased destruction
Sequestration (Hypersplenism)
Dilutional
Normal value 150K-300K
At what platelet count level does SPONTANEOUS bleeding generally occur? Ans: ~20K Platelets normally 150K-300K. This is one “normal range” you should memorize.

33. DE-CREASED PRODUCTION
APLASTIC ANEMIA
ACUTE LEUKEMIAS
ALCOHOL, THIAZIDES, CHEMO
MEASLES, HIV
MEGALOBLASTIC ANEMIAS
MYELODYSPLASTIC SYNDROMES (PRE-Leukemias)

34. IN-CREASED DESTRUCTION
AUTOIMMUNE (ITP)
POST-TRANSFUSION (NEONATAL)
QUINIDINE, HEPARIN, SULFA
MONO, HIV
DIC, “CONSUMPTIVE”
TTP/HUS
“MICROANGIOPATHIC”
Note the last three items are ALL in the same category. Are platelets low in a “consumption” coagulopathy? Answer: Yes!
What are the “consumable” clotting factors, classically? Answer: Platelets, fibrinogen, V, VIII

35. THROMBOCYTOPENIAS ITP (Idiopathic Thrombocytopenic Purpura)
Acute Immune
DRUG-induced
HIV associated
TTP, Hemolytic Uremic Syndrome
At what platelet count level does SPONTANEOUS bleeding generally occur? Ans: 20K Platelets normally 150K-300K

36. I.T.P. INCREASED MARROW MEGAKARYOCYTES ADULTS AND ELDERLY
ACUTE OR CHRONIC
AUTO-IMMUNE
ANTI-PLATELET ANTIBODIES PRESENT
INCREASED MARROW MEGAKARYOCYTES
Rx: STEROIDS
Any thrombocytopenia of increased destruction should have INCREASED megakaryocytes in the marrow! JUST LIKE a hemolytic anemia has an erythroid HYPER-plasia, same principle! Does this follow the pattern of a classic “autoimmune” disease? Yes!

37. ACUTE ITP CHILDREN Follows a VIRAL illness (~ 2 weeks)
ALSO have anti-platelet antibodies
Platelets usually return to normal in a few months
Remember MANY autoimmune diseases are triggered off by previous infections!

38. DRUGS
Quinine
Quinidine
Sulfonamide antibiotics
HEPARIN

39. HIV
BOTH DE-creased production AND IN-creased destruction factors are present

40. Thrombotic Microangiopathies
BOTH are very SERIOUS CONDITIONS with a HIGH mortality:
TTP (THROMBOTIC THROMBOCYTOPENIC PURPURA)
H.U.S. (HEMOLYTIC UREMIC SYNDROME)
These can also be called “consumptive” coagulopathies, just like a DIC
Most cases of TTP arise from inhibition of the enzyme ADAMTS13, a metalloprotease responsible for cleaving large multimers of von Willebrand factor (vWF) into smaller units. The increase in circulating multimers of vWF increase platelet adhesion to areas of endothelial injury, particularly at arteriole-capillary junctions.

41. “QUALITATIVE” platelet disorders
Mostly congenital (genetic):
Bernard-Soulier syndrome (Glycoprotein-1-b deficiency)
Glanzmann’s thrombasthenia (Glyc.-IIB/IIIA deficiency)
Storage pool disorders, i.e., platelets mis-function AFTER they degranulate
ACQUIRED: ASPIRIN, ASPIRIN, ASPIRIN
Platelet numbers may be normal but do not function well.

42. BLEEDING DISORDERS due to CLOTTING FACTOR DEFICIENCIES
NOT spontaneous, but following surgery or trauma
ALL factor deficiencies are possible
Factor VIII and IX both are the classic X-linked recessive hemophilias, A and B, respectively
ACQUIRED disorders often due to Vitamin-K deficiencies (II, VII, IX, X)
von Willebrand disease the most common, 1%
By the way, von Willebrand patients are ALWAYS on the step-1 exam.

43. von Willebrand Disease
1% prevalence, most common bleeding disorder
Spontaneous and wound bleeding
Usually autosomal dominant
Gazillions of variants, genetics even more complex
Prolonged BLEEDING TIME, NL platelet count
vWF is von Willebrand Factor, which complexes with Factor VIII, it is the von Willebrand Factor which is defective in von Willebrand disease
Usually BOTH platelet and FactorVIII-vWF disorders are present
Because von Willebrand is so closely linked to Factor VIII, it has also been called “pseudo”-hemophilia, but so have many other clotting disorders, so avoid using this term. What are prolonged bleeding times usually due to? Ans: Low Platelets!

44. PTT
PT/INR
Hypercoagulability is anything which accelerates the cascade (common), or inhibits its inhibitors (rare).

45. HEMOPHILIA A Prolonged PTT (intrinsic) only
The “classic” HEMOPHILIA
Factor VIII decreased
Co-factor of Factor IX to activate Factor X
Sex-linked recessive
Hemorrhage usually NOT spontaneous
Wide variety of severities
Prolonged PTT (intrinsic) only
Rx: Recombinant Factor VIII

46. HEMOPHILIA B Prolonged PTT (intrinsic) only The “Christmas” HEMOPHILIA
Factor IX decreased
Sex-linked recessive
Hemorrhage usually NOT spontaneous
Wide variety of severities
Prolonged PTT (intrinsic) only
Rx: Recombinant Factor IX
For all practical purposes, the same as Hemophilia A. How to differentiate? Factor assays! Note the AMAZING similarities between Hemophilia A and B

47. DIC, Disseminated INTRA-vascular, Coagulation
ENDOTHELIAL INJURY
WIDESPREAD FIBRIN DEPOSITION
HIGH MORTALITY
ALL MAJOR ORGANS COMMONLY INVOLVED
What is a “consumptive” coagulopathy? Ans: the platelets and many clotting factors are “consumed”, i.e., used up!

48. DIC, Disseminated INTRA-vascular, Coagulation
Extremely SERIOUS condition
NOT a disease in itself but secondary to many conditions
Obstetric: MAJOR OB complications, toxemia, sepsis, abruption
Infections: Gm-, meningococcemia, RMSF, fungi, Malaria
Many neoplasms, acute promyelocytic leukemia
Massive tissue injury: trauma, burns, surgery
“Consumptive” coagulopathy

49. Common Coagulation TESTS
PTT (intrinsic)
PT INR (extrinsic)
Platelet count, aggregation
Bleeding Time, so EASY to do
Fibrinogen
Factor Assays
Would you feel confident taking a patient to surgery if all these tests were normal, especially the first four? Answer: YES

50. RBC LAB http://www.chronolab.com/hematology/2_1.htm
Lets familiarize ourselves with all these abnormal RBC critters.